This Center for Cancer Nanotechnology Excellence for Translational Diagnostics (CCNE-TD) brings together scientists and physicians from Stanford University and the Massachusetts Institute of Technology to tackle the grand challenges of cancer early detection, image guided biopsy, monitoring response to therapy and early discrimination of aggressive vs. indolent disease. This research proposal is centered on our vision that in vitro diagnostics used in conjunction with in vivo molecular imaging can markedly impact future cancer patient management. Furthermore, we believe that nanotechnology can significantly advance both in vitro diagnostics through nanosensors, and in vivo diagnostics through nanoparticles for molecular imaging. The two major cancers that we will study are lung and prostate cancer. For lung cancer we will apply our technologies for early detection and to monitor response to therapy. For prostate cancer we will use our technologies to improve image guided biopsy, distinguish early aggressive vs. indolent cancers, and monitor response to therapy. We have assembled a highly interdisciplinary team of scientists with highly synergistic expertise and a long collaboration history. We will utilize significant resources at several small companies we have started and plan to further commercialize our most promising technologies. Project 1 focuses on the development of novel cancer triggered self-assembling and disassembling nanoparticles for positron emission tomography (PET) visualization of lung tumors and their response to chemotherapy. Project 2 focuses on the use of magneto- nanotechnology for blood biomarkers, single cell analysis of circulating tumor cells after enrichment and comprehensive analyses of blood-borne lung cancer markers. Project 3 focuses on the biophysical analysis of extracellular vesicles and their role in prostate cancer oncogenesis. Project 4 focuses on molecular imaging of prostate cancer with targeted nanobubbles for combined photoacoustic/ultrasound imaging and self-assembling nanoparticles for photoacoustic imaging. The Administrative Core will facilitate progress towards our milestones, Core 1 will provide resources for nano characterization and fabrication, and Core 2 will facilitate clinical translation by linking our nanotechnologies to existing patient samples, ad ongoing/new clinical trials. Leveraged access to clinical samples and studies include several large clinical trials for lung cancer (MD Anderson Lung Cancer Early Detection Moonshots Program), prostate cancer (The Prostate Active Surveillance Study (PASS) run by the Canary Foundation), and the Stanford-Google[X]- Duke baseline study to study the transition from health to illness in 10,000 individuals being launched in 2015. With our highly interactive and cohesive program focused on developing and validating nanotechnology for earlier cancer detection and prognostication, improved image guided biopsies, anti- cancer therapy response, we will imagine, invent, innovate, and translate.